Specificity and memory are key features of the adaptive immune system (Bonilla et al. (2010) J. Allergy Clin. Immunol. 125:S33-S40; Litman et al. (2010) Nat. Rev. Immunol. 10:543-553). An adaptive immune response amplifies a small population of antigen (Ag) specific B and T lymphocytes to promote the clearance of an infection. Although B cell receptors (antibodies) can recognize soluble intact Ag, T cells recognize cognate peptides presented in the context of major histocompatibility complex (MHC) molecules on the surface of antigen presenting cells (APCs) (Davis et al. (1988) Nature 334:395-402).
Antibodies have exquisite specificity for their antigen. Thus, antibodies have great therapeutic potential in terms of selectively targeting receptors to either promote or inhibit receptor activity. Likewise, antibodies can target infected or tumor cells by recognizing their antigen on the cell of interest. However, the exquisite specificity imparted by the antibody-antigen interaction can be abrogated by the expression of the target receptor on “off target” cells. For example, soluble anti-CD3 will activate all T cells, not just the T cells of interest. Likewise, anti-CTLA-4 and anti-PD-1 will block these molecules on all T cells, not just the T cells of interest. In fact, a major hurdle for anti-CD3 agonistic and anti-PD-1 (and anti-CTLA-4) antibodies is that they cause non-specific T cell activation and at times life threatening autoimmunity.
The concept of the dichotomy of selective target specificity in the absence of cellular specificity can also be extended generically to receptor-ligand interactions. In other words, the administration of a ligand might have great specificity for a receptor, but if the receptor is found both on cells of interest and “normal” cells, this specificity is in part negated (Lim and Levy (2014) J. Immunol. 193(4):1519-24).
A fundamental tenet of immunotherapy for cancer is the ability of effectors of the immune system to specifically target cancer cells, while leaving normal cells unscathed. In spite of tremendous advances in understanding antigen specificity and developing vaccines, until very recently immunotherapy for cancer has not lived up to its potential. This is because tumors develop means to evade the endogenous immune destruction by usurping negative regulatory pathways inherent to the immune response. Blocking these pathways with anti-CTLA-4 and anti-PD-1 antibodies, so called checkpoint blockade, has led to meaningful clinical responses in patients. The utility of this strategy is limited, in part, however, by the fact that checkpoint blockade non-selectively enhances T cell responses thus leading to autoimmunity. A strategy that promotes checkpoint blockade for anti-tumor responses without non-selectively activating the immune system is desirable.